College of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
J Immunol. 2010 Nov 15;185(10):6329-37. doi: 10.4049/jimmunol.1001213. Epub 2010 Oct 15.
Mast cells are effector cells that mediate the allergic response through Ag stimulation of IgE bound to FcεRI. In allergic reactions, cross-linking of the surface receptors for IgE on mast cells results in the synthesis of Th2 cytokines such as IL-4 and IL-13, which are critical for the initiation and progression of the allergic response. Despite the important roles of these cytokines, the signaling mechanism by which Ag stimulation mediates the production of IL-4 and IL-13 in mast cells is not clearly understood. In the present study, we found that Ag-stimulated bone marrow-derived mast cells (BMMCs) highly upregulated the expression of BLT2, a leukotriene B(4) receptor, and that blockade of BLT2 with the specific antagonist LY255283 or small interfering RNA knockdown completely abolished the production of Th2 cytokines. Furthermore, BMMCs overexpressing BLT2 showed significantly enhanced production of Th2 cytokines compared with wild-type BMMCs. Additionally, we found that the generation of Nox1-derived reactive oxygen species occurs downstream of BLT2, thus mediating the synthesis of Th2 cytokines. Taken together, our results suggest that the BLT2-Nox1-reactive oxygen species cascade is a previously unsuspected mediatory signaling mechanism to Th2 cytokine production in Ag-stimulated BMMCs, thus contributing to allergic response.
肥大细胞是效应细胞，通过 Ag 刺激 IgE 与 FcεRI 结合来介导过敏反应。在过敏反应中，肥大细胞表面 IgE 受体的交联导致 Th2 细胞因子（如 IL-4 和 IL-13）的合成，这些细胞因子对于过敏反应的启动和进展至关重要。尽管这些细胞因子具有重要作用，但 Ag 刺激介导肥大细胞中 IL-4 和 IL-13 产生的信号机制尚不清楚。在本研究中，我们发现 Ag 刺激的骨髓来源的肥大细胞（BMMC）高度上调了 BLT2 的表达，BLT2 是一种白三烯 B4 受体，而特异性拮抗剂 LY255283 或小干扰 RNA 敲低阻断 BLT2 完全消除了 Th2 细胞因子的产生。此外，过表达 BLT2 的 BMMC 与野生型 BMMC 相比，Th2 细胞因子的产生明显增强。此外，我们发现 BLT2 下游发生了 Nox1 衍生的活性氧的生成，从而介导了 Th2 细胞因子的合成。综上所述，我们的结果表明，BLT2-Nox1-活性氧级联是 Ag 刺激的 BMMC 中 Th2 细胞因子产生的一种以前未被怀疑的中介信号机制，从而有助于过敏反应。
